A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo

Publication date: 11 November 2019Source: Cancer Cell, Volume 36, Issue 5Author(s): Longchuan Bai, Haibin Zhou, Renqi Xu, Yujun Zhao, Krishnapriya Chinnaswamy, Donna McEachern, Jianyong Chen, Chao-Yie Yang, Zhaomin Liu, Mi Wang, Liu Liu, Hui Jiang, Bo Wen, Praveen Kumar, Jennifer L. Meagher, Duxin Sun, Jeanne A. Stuckey, Shaomeng WangSummarySignal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. Here we report the discovery of SD-36, a small-molecule degrader of STAT3. SD-36 potently induces the degradation of STAT3 protein in vitro and in vivo and demonstrates high selectivity over other STAT members. Induced degradation of STAT3 results in a strong suppression of its transcription network in leukemia and lymphoma cells. SD-36 inhibits the growth of a subset of acute myeloid leukemia and anaplastic large-cell lymphoma cell lines by inducing cell-cycle arrest and/or apoptosis. SD-36 achieves complete and long-lasting tumor regression in multiple xenograft mouse models at well-tolerated dose schedules. Degradation of STAT3 protein, therefore, is a promising cancer therapeutic strategy.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research